Methods of preparing co-crystals of ibrutinib with carboxylic acids

ABSTRACT

The present invention relates to co-crystals of ibrutinib and a pharmaceutical composition comprising the same as well as a method of preparing the same.

PRIORITY

This application is a divisional of U.S. application Ser. No. 15/559,410filed Sep. 18, 2017, which corresponds to the U.S. national phase ofInternational Application No. PCT/EP2016/056312, filed Mar. 23, 2016,which, in turn, claims priority to European Patent Application Nos.15.000976.9 filed Apr. 2, 2015; 15.179523.4 filed Aug. 3, 2015; and15.020227.3 filed Nov. 16, 2015, the contents of which are incorporatedby reference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to co-crystals of ibrutinib, a method ofpreparing the same as well as a pharmaceutical composition comprisingthe same.

BACKGROUND OF THE PRESENT INVENTION

Ibrutinib(1-[(3R)-3[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-lone) has the following chemical structure (I):

This pharmaceutically active ingredient is known from WO 2008/039218.Ibrutinib is an inhibitor of bruton's tyrosine kinase (BTK). BTK is akey mediator of at least three critical B-cell pro-survival mechanismsoccurring in parallel regulating B-cell apoptosis, cell adhesion andlymphocyte migration and homing. By inhibiting BTK ibrutinib drivesB-cells into apoptosis and/or disrupts cell immigration and adherence totumor-protective microenvironments. Ibrunitib is therefore suitable fortreating chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma(SLL) which are B-cell non-hodgkin lymphomas (NHL) and mantle celllymphoma (MCL). It is marketed in the US under the name Imbruvica.

Crystalline polymorphic forms of ibrutinib are disclosed in WO2013/184572.

Pharmaceutical formulations comprising ibrutinib are disclosed in WO2014/004707A1.

Ibrutinib has a very low solubility in water e.g. form A of ibrutinibshows according to WO 2013/184572, an observed aqueous solubility ofonly about 0.013 mg/ml at about pH 8. The solubility strongly depends onthe pH. This results in problems in the bioavailability of the activeingredient, first because of the low solubility, and second itssolubility depends on the pH value in the stomach of the patient.Particular problems arise from patients wherein the pH value is altered,e.g. due to physiological variability, diseases or premedication such asPP-inhibitors. Ibrutinib has been classified as a BCS class 2 drug andtherefore, the absorption and bioavailability is primarily determined byits dissolution under physiological conditions.

WO 2013/184572, discloses further the preparation of six differentcrystalline forms of ibrutinib base. The existence of amorphousibrutinib has also been mentioned but no details regarding preparationor properties are described. Three of the crystalline forms, i.e. formA, B and C are anhydrous, non-solvated forms while forms D, E and Fcontain either methyl isobutyl ketone, toluene or methanol,respectively.

To investigate the impact of crystalline form on physico-chemicalproperties, some crystalline forms of ibrutinib base, i.e. form A, formB, form C as well as amorphous ibrutinib base were prepared andcharacterized. Form C and amorphous ibrutinib showed substantiallyhigher aqueous solubility compared to form A, but while stirring insuspension, a conversion into the less soluble form A was observed.

Therefore, due to the described complex polymorphism of ibrutinib baseand the significant impact of solid state form on dissolution andsolubility, new pharmaceutically applicable forms of ibrutinib might beuseful as alternative active pharmaceutical ingredients.

Further, amorphous forms may be very difficult to purify since simpleprocess steps like filtration or recrystallization normally do not work.Furthermore, it is very difficult to guarantee content uniformity forthe active substance when processed in amorphous form into the finalsolid formulation. Thus amorphous forms are typically not preferred forproduction of tablet formulations.

SUMMARY OF THE INVENTION

It has now surprisingly been found that ibrutinib forms stableco-crystals with organic acids which carry one or more carboxylategroup(s), or carboxyl amides.

The present invention therefore relates to co-crystals of ibrutinib anda carboxylic acid or carboxylic amide.

Suitable carboxylic acids are for example benzoic acid, fumaric acid andsuccinic acid as well as those acids exemplified in the description ofthe method below. Suitable carboxyl amide is for example urea ornicotine amide.

The present invention also relates to a method for preparing co-crystalsof ibrutinib comprising the steps of a) suspending ibrutinib with acarboxylic acid in a suitable solvent, preferably an organic solvent, b)heating the obtained suspension till a clear solution is obtained,optionally keeping the temperature for some time and/or under stirring,and c) subsequently cooling the solution of ibrutinib to roomtemperature, while a solid started to precipitate or started tocrystallize. The resulting precipitate or crystals can finally beisolated.

In the method of the present invention in step a) any carboxylic acidcan be used which is known to the skilled person. Preferably, acarboxylic acid such as glutamic acid, aspartic acid, malonic acid,adipic acid, nicotinic acid, maleic acid, 3-hydroxybenzoic acid,4-hydroxybenzoic acid, terephthalic acid, L-tartaric acid, D-tartaricacid, L-malic acid, D-malic acid, succinic acid, oxalic acid, benzoicacid, fumaric acid or citric acid can be used.

In an alternative method of the present invention in step a) anycarboxyl amide can be used which are known to the skilled person.Preferably, a carboxyl amide such as urea or nicotine amide can be used.

In the method of the present invention in step a) any suitable solventfor ibrutinib can be used which are known to the skilled person.Preferably, an organic solvent, more preferably a polar organic solvent,such as dichloromethane, chloroform, tetrahydrofuran (THF) or methanolcan be used. Most preferably ibrutinib is dissolved in an aliphaticC₁-C₆ alcohol, such as methanol.

In a further aspect, an organic solvent such as methyl tert.-butyl ethercan be used.

In the method of the present invention in step a) the molar ratio ofcarboxylic acid to ibrutinib is typically equal to or above 1,preferably in the range of 1 to 2, more preferably 1 to 1.5, even morepreferred 1 to 1.3, in particular 1 to 1.2, e.g. about 1.

The method of the present invention surprisingly allows preparingco-crystals of ibrutinib preferably in good crystalline quality withadvantageous handling properties such as good flowablility, inparticular suitable for pharmaceutical compositions, which also have animproved solubility or equal solubility compared to ibrutinib free base.

The method of the present invention surprisingly allows preparingco-crystals of ibrutinib preferably in a single, stable solid form whichdoes not undergo changes in physical characteristics such as differentsolid forms.

A solid state form may be referred to herein as being characterized bydata selected from two or more different data groupings, for example, bya powder XRD pattern having a group of specific peaks; or by a powderXRD pattern as shown in a figure depicting a diffractogram, or by “acombination thereof (or “combinations thereof,” or “any combinationthereof”). These expressions, e.g., “any combination thereof”contemplate that the skilled person may characterize a crystal formusing any combination of the recited characteristic analytical data. Forexample, the skilled person may characterize a crystal form using agroup of three, four or five characteristic powder XRD peaks, andsupplement that characterization with one or more additional featuresobserved in the powder X-ray diffractogram, e.g., an additional peak, acharacteristic peak shape, a peak intensity, or even the absence of apeak at some position in the powder XRD pattern. Alternatively, theskilled person may in some instances characterize a crystal form using agroup of three, four or five characteristic powder XRD peaks andsupplement that characterization with one or more additional featuresobserved using another analytical method, for example, using one or morecharacteristic peaks in a solid state IR spectrum, or characteristics ofthe DSC thermogram of the crystal form that is being characterized.

Unless indicated otherwise, XRPD peaks are recorded using copper Kα₁/Kα₂radiation with wavelength 1.5419 Å (weighted mean of Cu Kα₁ and Cu Kα₂).Further, unless indicated otherwise, XRPD peaks are reported as degrees2-theta values with standard errors of ±0.2 degrees 2-theta.

A crystal form may be referred to herein as being characterized bygraphical data “as depicted in” a particular figure. Such data include,for example, powder X-ray diffractograms.

The skilled person will understand that such graphical representationsof data may be subject to small variations, e.g., in peak relativeintensities and peak positions due to factors such as variations ininstrument response and variations in sample concentration and purity,which are well known to the skilled person. Nonetheless, the skilledperson would readily be capable of comparing the graphical data in thefigures herein with graphical data generated for an unknown crystal formand confirm whether the two sets of graphical data are characterizingthe same crystal form or two different crystal forms.

In one preferred embodiment the present invention relates to aco-crystal of ibrutinib and benzoic acid (ibrutinib:benzoic acid).Ibrutinib:benzoic acid is characterized by a ¹H-NMR spectrum showing thefollowing signals (*=signals of benzoic acid): 1.57 (br. s., 1H);1.84-1.97 (m, 1H); 2.12 (br. s., 1H); 2.25 (qd, J=11.93, 4.11 Hz, 1H);2.86-3.09 (m, 1H); 3.11-3.26 (m, 1H); 3.30 (br. s., 1H); 3.53-3.77 (m,1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s., 1H); 4.54 (d, J=11.34 Hz,1H); 4.70 (br. s., 1H); 5.57 (d, J=9.78 Hz, 1H); 5.69 (d, J=10.17 Hz,1H); 6.00-6.21 (m, 1H); 6.51-6.77 (m, 1H); 6.77-7.02 (m, 1H); 7.09-7.19(m, 5H); 7.39-7.51 (m, 4H(2H*)); 7.54-7.73 (m, 3H(1H*)); 7.91-7.96 (m,2H)*; 8.24 (s, 1H); 12.93 (br. s., 1H*). A ¹H-NMR spectrum of ibrutinibbenzoic acid is shown in FIG. 1.

In one embodiment of the present invention ibrutinib:benzoic acid ischaracterized by the following XRPD diffraction peaks: 9.1, 12.1, 13.7,13.9 and 23.0 or 15.1, 18.2, 21.2, 23.0 and 27.9 or 15.1, 18.3, 21.2,23.0 and 27.9 degrees 2-theta±0.2 degrees 2-theta.

In a preferred embodiment of the present invention ibrutinib:benzoicacid is characterized further by the following XRPD diffraction peaks:16.1, 16.2, 19.1, 20.1 and 21.2 or 9.1, 12.1, 22.1, 23.9 and 30.3 or9.1, 12.1, 22.1, 23.9 and 30.2 degrees 2-theta±0.2 degrees 2-theta.

In a further preferred embodiment of the present inventionibrutinib:benzoic acid is characterized by the following XRPDdiffraction peaks: 9.1, 12.1, 13.7, 13.9 and 23.0 degrees 2-theta±0.2degrees 2-theta and further characterized by one or more peaks at 15.1,16.1, 16.2, 17.3, 18.2, 19.1, 19.5, 20.1, 21.2, 22.1, 23.9, 24.4, 25.8,27.9, 28.6, 29.1 and 30.3 degrees 2-theta±0.2 degrees 2-theta.

An XRPD diffraction pattern of ibrutinib:benzoic acid is shown in FIG. 2and FIG. 3.

In another preferred embodiment the present invention relates to aco-crystal or ibrutinib and fumaric acid (ibrutinib:fumaric acid).Ibrutinib:fumaric acid is characterized by a ¹H-NMR spectrum showing thefollowing signals (*=signals of fumaric acid): 1.57 (br. s., 1H);1.75-2.01 (m, 1H); 2.11 (br. s., 1H); 2.18-2.46 (m, 1H); 2.65 (s, 1H);3.01 (d, J=9.78 Hz, 1H); 3.20 (br. s., 1H); 3.68 (br. s., 1H); 4.06 (d,J=12.12 Hz, 1H); 4.19 (br. s., 1H); 4.52 (br. s., 1H); 4.69 (br. s.,1H); 5.57 (d, J=10.17 Hz, 1H); 5.69 (d, J=11.34 Hz, 1H); 5.99-6.19 (m,1H); 6.52-6.63 (m, 1H*); 6.64-6.77 (m, 1H); 6.78-6.98 (m, 1H); 7.09-7.19(m, 4H); 7.31-7.53 (m, 2H); 7.64 (d, J=7.82 Hz, 2H); 8.24 (s, 1H); 13.10(br. s., 1H*). A ¹H-NMR spectrum of ibrutinib:fumaric acid is shown inFIG. 6.

In one embodiment of the present invention ibrutinib:fumaric acid ischaracterized by the following XRPD diffraction peaks: 9.9, 17.4, 18.7,20.5 and 21.7 or 17.4, 18.2, 20.5, 21.7 and 23.9 degrees 2-theta±0.2degrees 2-theta.

In a preferred embodiment of the present invention ibrutinib:fumaricacid is characterized further by the following XRPD diffraction peaks:6.5, 13.0, 18.2, 22.4 and 23.9 or 6.5, 9.9, 25.7, 28.1 and 29.3 degrees2-theta±0.2 degrees 2-theta.

In a further preferred embodiment of the present inventionibrutinib:fumaric acid is characterized by the following XRPDdiffraction peaks: 9.9, 17.4, 18.7, 20.5 and 21.7 degrees 2-theta±0.2degrees 2-theta and further characterized by one or more peaks at 6.5,10.1, 10.5, 10.8, 11.9, 12.6, 12.8, 13.0, 14.7, 15.2, 18.2, 19.8, 21.0,22.4, 25.7, 26.8, 28.1, and 29.3 degrees 2-theta±0.2 degrees 2-theta.

An XRPD diffraction pattern of ibrutinib:fumaric acid is shown in FIG.7.

In another preferred embodiment the present invention relates to aco-crystal of ibrutinib and succinic acid (ibrutinib:succinic acid).Ibrutinib:succinic acid is characterized by a ¹H-NMR spectrum showingthe following signals (*=signals of succinic acid): 1.57 (br. s., 1H);1.92 (d, J=13.69 Hz, 1H); 2.12 (br. s., 1H); 2.18-2.32 (m, 1H);2.38-2.42 (m, 3H*); 2.88-3.07 (m, 1H); 3.10-3.27 (m, 1H); 3.70 (d,J=10.56 Hz, 1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s., 1H); 4.54 (d,J=12.12 Hz, 1H); 4.69 (br. s., 1H); 5.57 (d, J=9.78 Hz, 1H); 5.69 (d,J=10.56 Hz, 1H); 6.00-6.18 (m, 1H); 6.54-6.77 (m, 1H); 6.77-6.98 (m,1H); 7.09-7.20 (m, 5H); 7.33-7.51 (m, 2H); 7.65 (d, J=7.82 Hz, 2H) 8.24(s, 1H); 12.10 (br. s., 1H*). A 1H-NMR spectrum of theibrutinib:succinic acid co-crystal is shown in FIG. 10.

In one embodiment of the present invention ibrutinib:succinic acid ischaracterized by the following XRPD diffraction peaks: 17.3, 17.9, 20.2,21.5 and 21.8 degrees 2-theta±0.2 degrees 2-theta.

In a preferred embodiment of the present invention ibrutinib:succinicacid is characterized further by the following XRPD diffraction peaks:9.8, 11.5, 13.0, 18.3 and 23.2 degrees 2-theta±0.2 degrees 2-theta.

In a further preferred embodiment of the present inventionibrutinib:succinic acid is characterized by the following XRPDdiffraction peaks: 17.3, 17.9, 20.2, 21.5 and 21.8 degrees 2-theta±0.2degrees 2-theta and further characterized by one or more peaks at 6.5,9.8, 10.2, 10.8, 11.5, 12.5, 13.0, 14.7, 15.2, 15.7, 18.3, 19.7, 23.2,23.8, 24.2, 25.1, 26.1, 26.7, 27.2, 28.6 and 29.0 degrees 2-theta±0.2degrees 2-theta.

An XRPD diffraction pattern of ibrutinib:succinic acid is shown in FIG.11.

The present invention furthermore relates to a pharmaceuticalpreparation comprising a co-crystal of ibrutinib according to thepresent invention, in particular a co-crystal of ibrutinib as definedabove. In a preferred embodiment, the present invention relates to apharmaceutical preparation comprising a co-crystal of ibrutinib withbenzoic acid, with fumaric acid or with succinic acid. Thepharmaceutical preparation of the present invention preferably is anoral solid preparation, such as a capsule or tablet.

The pharmaceutical preparation can additionally contain one or morepharmaceutically acceptable excipients, such as fillers, binder,glidants, disintegrants, flow regulating agents and release agents.Suitable excipients are for example disclosed in “Lexikon derHilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete”, publishedby H. P. Fielder, 4^(th) Edition and “Handbook of PharmaceuticalExcipients”, 3^(1d) Edition, published by A. H. Kibbe, AmericanPharmaceutical Association, Washington, USA, and Pharmaceutical Press,London.

Suitable fillers are for example lactose and calcium hydrogen phosphate.Fillers can be present in an amount of 0-80% by weight, preferably in anamount of 10-60% by weight of the total weight of the composition.

Suitable binders are for example polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, sugars, dextran, corn starch. Binders can be present in anamount of 0-80% by weight, preferably in an amount of 10-60% by weightof the total weight of the composition.

Suitable glidants are for example alkaline earth metal salts of fattyacids, like stearic acid. The glidant can be present for example in anamount of 0-2% by weight, preferably in an amount of 0.5-1.5% by weightof the total weight of the composition.

Suitable disintegrants are for example crosscarmelose sodium, sodiumcarboxymethyl starch, crosslinked polyvinylpyrrolidone (crosspovidone),sodium carboxymethylglycolate (such as Explotab) and sodium bicarbonate.The disintegrant can be present in an amount of 0-20% by weight,preferably in an amount of 1-15% by weight of the total weight of thecomposition.

A suitable flow regulating agent is for example colloidal silica. Theflow regulating agent can be present in an amount of 0-8% by weight,preferably in an amount of 0.1-3% by weight of the total weight of thiscomposition.

A suitable release agent is for example talcum. The release agent can bepresent in an amount of 0-5% by weight, preferably in an amount of0.5-3% by weight of the total weight of the composition.

The solid preparation, preferably a tablet or a capsule can be coated,preferably film coated.

A suitable coating agent are for example cellulose derivatives,poly(meth)acrylate, polyvinyl pyrrolidone, polyvinyl acetate phthalate,and/or shellac or natural rubbers such as carrageenan.

The pharmaceutical preparation of the present invention can be preparedby methods well known to a person skilled in the art.

The present invention relates further to the use of a co-crystal ofibrutinib for preparing a pharmaceutical preparation for the treatmentof patients with mantle cell lymphoma (MCL), small lymphocytic lymphoma(SLL) and chronic lymphocytic leukemia (CLL).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the ¹H-NMR spectrum of ibrutinib:benzoic acid co-crystal(1:1) (¹H-NMR in DMSO-d₆, 400 MHz).

FIG. 2 shows the XRPD diffractogram of ibrutinib:benzoic acid co-crystal(1:1).

FIG. 3 shows an XRPD diffractogram of ibrutinib:benzoic acid co-crystal(1:1) (at the top) compared with a simulated powder diffractogramproduced from the atomic positions resulting from the three-dimensionalx-ray structure of ibrutinib:benzoic acid co-crystal (1:1).

FIG. 4 shows an UHPLC/UV analysis of ibrutinib:benzoic acid (1:1)co-crystal. Signal at Rt=2.49 min corresponds to benzoic acid.

FIG. 5 shows the position of benzoic acid bound through hydrogen bondsto ibrutinib base as observed in the three-dimension crystal structureanalysis of a single crystal on ibrutinib:benzoic acid co-crystal (1:1).

FIG. 6 shows the ¹H-NMR spectrum of ibrutinib:fumaric acid co-crystal(2:1) (¹H-NMR in DMSO-d₆, 400 MHz).

FIG. 7 shows the XRPD diffractogram of ibrutinib:fumaric acid co-crystal(2:1).

FIG. 8 shows an UHPLC/UV analysis of ibrutinib:fumaric acid (2:1)co-crystal. Signal at Rt=1.67 min corresponds to fumaric acid.

FIG. 9 shows the position of fumaric acid bound through hydrogen bondsto ibrutinib base as observed in the three-dimension crystal structureanalysis of a single crystal on ibrutinib:fumaric acid co-crystal (2:1).

FIG. 10 shows the ¹H-NMR spectrum of ibrutinib:succinic co-crystal(¹H-NMR in DMSO-d₆, 400 MHz).

FIG. 11 shows the XRPD diffractogram of ibrutinib:succinic acidco-crystal.

FIG. 12 shows an UHPLC/UV analysis of ibrutinib:succinic acidco-crystal.

FIG. 13 shows the position of succinic acid bound through hydrogen bondsto ibrutinib base as observed in the three-dimensional crystal structureanalysis of a single crystal on ibrutinib:succinic acid co-crystal(2:1).

FIG. 14 shows the XRPD diffractogram of ibrutinib:fumaric co-crystalafter stress testing.

FIG. 15 shows the XRPD diffractograms of ibrutinib co-crystals comparedto ibrutinib form E, each before and after storage for 12 weeks.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Analytical Methods

¹H-NMR Spectroscopy

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400MHz.

UHPLC/UV

Instrument: Agilent 1290 Infinity

Wavelength 258 nm

Column: Kinetex C18 150×4.6 mm, 6 μm

Column temp.: 40° C.

Injection volume: 1 μl

Solvent A: acetonitrile

Solvent B: 0.2% formic acid+0.1% heptafluorobutyric acid

Flow: 0.8 ml/min

time [min] solvent B [%] 0.00 55 10.00 10 12.00 10 12.50 55

X-Ray Powder Diffraction (XRPD)

First Method:

The samples were measured on a D8 Advance powder X-ray diffractometer(Bruker AXS, Karlsruhe, Germany) in a rotating PMMA sample holder(diameter: 25 mm; depth: 1 mm) in reflection mode (Bragg-Brentanogeometry). Conditions of the measurements are summarized in the tablebelow. Raw data were analyzed with the program EVA (Bruker AXS,Karlsruhe, Germany).

radiation Cu Kα₁/α₂ source 34 kV/40 mA detector Vantec-1 (electronicwindow: 3°) Kβ filter Ni (diffracted beam) measuring circle diameter 435mm detector window slit 12 mm anti-scatter slit (diffracted beam) 8 mmdivergence slit v6.00 (variable) Soller slit (incident/diffracted beam)2.5° 2θ range 2° ≤ 2θ ≤ 55° step size 0.016 step time 0.2 s

Second Method (for Stress Testing):

The analysis of was performed on ARL (SCINTAG) powder X-Raydiffractometer model X′TRA equipped with a solid stage detector. Copperradiation of 1.5418 Å was used.

Scanning parameters: range: 2-40 degrees two-theta; scan mode:continuous scan; step size: 0.05°, and a rate of 3 deg/min.

X-Ray Singe Crystal Diffraction (XRD)

The crystal was measured on an Oxford Diffraction XCALIBURdiffractometer with area detector at 180 K with a wavelength of 1.54180Å.

For the following experiments and examples, the starting compoundibrutinib form A was obtained as described in WO 2013/184572.

Example 1: Preparation of Ibrutinib:Benzoic Acid Co-Crystal (1:1)Experiment 1

204 mg (0.46 mmol) ibrutinib form A was suspended together with 56 mg(0.46 mmol) benzoic acid in 1 mL MeOH at room temperature (RT). Thesuspension was heated to 75° C. A clear solution was obtained. Thesolution was let slowly cooled down to RT while a white solid started toprecipitate. The precipitate was isolated by filtration and dried at 50°C. /10 mbar for 24 hours (Yield: 65%).

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

Experiment 2

204 mg (0.46 mmol) ibrutinib form A was suspended together with 56 mg(0.46 mmol) benzoic acid in 1 mL MeOH at 30° C. After stirring, a clearsolution was obtained. The solution was let stirring for 60 minuteswhile a white solid started to precipitate. The precipitate was isolatedby filtration and dried at 50° C./10 mbar for 24 hours (Yield: 45%). Thesample was analysed by means of XRPD and ¹H-NMR spectroscopy.

Experiment 3

2,4 g (5.5 mmol) ibrutinib form A was suspended together with Benzoicacid 0.67 g (5.5 mmol) in MeOH (50 mL) at 30° C. After stirring of thesuspension a clear solution was obtained. The solution was let evaporatein rotavap until an approximately volume of 10 mL. A white solid startedto precipitate. The solution was let overnight with stirring at 30° C.for the complete precipitation. It was isolated by filtration and driedat 40° C./10 mbar for 72 hours. (Yield: 68%).

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

The results of Experiments 1 to 3:

¹H-NMR Spectroscopy

The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent,DMSO-d₆ was used. The ¹H-NMR spectrum is shown in FIG. 1. The signalsare summarized below (*=signals of benzoic acid):

1.57 (br. s., 1H); 1.84-1.97 (m, 1H); 2.12 (br. s., 1H); 2.25 (qd,J=11.93, 4.11 Hz, 1H); 2.86-3.09 (m, 1H); 3.11-3.26 (m, 1H); 3.30 (br.s., 1H); 3.53-3.77 (m, 1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s., 1H);4.54 (d, J=11.34 Hz, 1H); 4.70 (br. s., 1H); 5.57 (d, J=9.78 Hz, 1H);5.69 (d, J=10.17 Hz, 1H); 6.00-6.21 (m, 1H); 6.51-6.77 (m, 1H);6.77-7.02 (m, 1H); 7.09-7.19 (m, 5H); 7.39-7.51 (m, 4H(2H*)); 7.54-7.73(m, 3H(1H*)); 7.91 -7.96 (m, 2H)*; 8.24 (s, 1H); 12.93 (br. s., 1H*).

The integration values of the 1.93 ppm signal (1H) of ibrutinib and the2 orto-hydrogens from benzoic acid (7.93 ppm) were 1 and 2 resp. Itcorresponds with a ibrutinib:benzoic acid=1:1 molar ratio.

X-Ray Powder Diffraction (XRPD)

The product was characterized by means of x-ray powder diffraction. Itis shown in the FIG. 2.

most characteristic peaks [° 2θ] ± 0.2 ° 2θ sample Primarycharacterising peaks Secondary characterising peaks ibrutinib:benzoicacid (1:1) 9.1 12.1 13.7 13.9 23.0 16.1 16.2 19.1 20.1 21.2

The complete list of XRPD diffraction peaks of ibrutinib benzoic acidco-crystal (1:1):

Angle Relative Intensity ° (2Θ) % 9.1 12.5% 12.1 17.9% 13.7 3.9% 13.95.3% 15.1 23.9% 16.1 5.9% 16.2 3.6% 17.3 7.1% 18.2 19.8% 19.1 7.7% 19.54.5% 20.1 4.7% 21.2 24.0% 22.1 7.9% 23.0 100.0% 23.9 17.7% 24.4 6.5%25.8 2.3% 27.9 27.6% 28.6 5.2% 29.1 1.3% 30.3 8.9% 31.3 2.5% 32.5 2.3%33.6 2.4% 34.9 2.0% 35.3 1.8% 35.8 2.6% 36.7 3.1% 38.0 2.1% 39.2 1.7%40.2 1.7% 42.8 3.5% 43.8 2.2% 45.3 1.2% 45.9 1.1% 46.9 1.2% 47.9 2.7%49.9 2.8%

Also a comparative of this diffractogram with the simulated powderpattern from the single-crystal study results is shown in FIG. 3.

UHPLC/UV

The chromatogram from UHPLC/UV analysis is shown in FIG. 4. Noimpurities were detected (Rt=2.486 min: benzoic acid; Rt=3.763 min:ibrutinib).

Storage Stability of Ibrutinib:Benzoic Acid

One batch of the ibrutinib:benzoic acid cocrystal (stability batch) wasstored in open and closed containers in a climate chamber at 40° C./75%relative humidity (“accelerated conditions”). After storage for 4, 8 and12 weeks, samples were analyzed by UHPLC/UV (chemical purity) as well asby XRPD (solid state stability). The results of UHPLC/UV analysis,summarized in the following table demonstrate that the chemical purityof the ibrutinib:benzoic acid cocrystal remained unchanged.

Conditions (40° C./75% RH) Open Close 4 Weeks 99.74% 99.90% 8 Weeks99.77% 99.90% 12 Weeks  99.80% 99.91%

The results of XRPD analysis confirmed that the solid state of theibrutinib:benzoic acid cocrystal remained unchanged during storage underaccelerated conditions.

X-Ray Single Crystal Study of Ibrutinib:Benzoic Acid Co-Crystal (1:1)

The absolute configuration of the determined molecular structure matchedthe expected configuration, the Flack parameter was refined to a valueof 0.04(13), thus it corroborates the assignment. Hydrogen atoms wererefined according to a riding model with exception of heteroatom-bondedhydrogen atoms whose positions were refined without restraints.

Empirical formula C₃₂H₃₀N₆O₄ Formula weight 562.63 Temperature 180 KWavelength 1.54180 Å Crystal system triclinic Space group P1 Unit celldimensions a [Å] 7.3974(2) b [Å] 9.7644(2) c [Å] 9.9369(2) α [°]82.965(2) β [°] 81.427(2) γ [°] 88.055(2) Volume [Å³] 704.30(1) Z 1Density (calculated) [g · cm⁻³] 1.326 Absorption coefficient [mm⁻¹]0.731 F(000) 296 Crystal size [mm] 0.72 × 0.47 × 0.38 Theta range fordata collection 4.53 to 77.22 Index ranges −9 ≤ h ≤ 9, −12 ≤ k ≤ 12, −12≤ l ≤ 12 Reflections collected 22735 Independent reflections [R(int)]5472 (0.047) Completeness to Theta = 77.22° 97.8% Absorption correctionSemi-empirical from equivalents Max. and min. transmission 0.76 and 0.20Refinement method Full-matrix least-squares on F²Data/parameters/restraints 5467/390/8 Goodness-of-fit on F² 0.9338 FinalR indices [I > 2σ(I)] R₁ = 0.0343, wR₂ = 0.0922 Flack parameter 0.04(13)Final R indices [all data] R₁ = 0.0351, wR₂ = 0.0944 Largest diff. peakand hole 0.18 and −0.15 [e · Å⁻³]

As is shown in FIG. 5, the packing of ibrutinib:benzoic acid co-crystal,consist in 1 molecule of ibrutinib and 1 molecule of Benzoic acid, i.e.a molar ratio of 1:1 with a triclinic symmetry.

There are three hydrogen bonds in the structure.

Firstly, the H-bond between ibrutinib and benzoic acid (O4-H45 . . . N5)what confirms that the new solid state is a co-crystal, instead of abenzoate salt of ibrutinib. If the carboxyl group were deprotonated, theelectrons would delocalize, causing almost same length of both C˜O bonds(C26-O3 and C26-O4 in FIG. 5b ). In this case, it is clear that thecarboxyl group is protonized, as there is a distance C═O of 1.219(2) Å(C26-O3) and C—O—H, with C—O 1.313(2) Å (C26-O4). The carboxyl protonwas located in difference Fourier map and its position was refinedwithout restraints.

Secondly, H-bond between ibrutinib and benzoic acid (N4-H . . . O3) is asoft-moderate H-bond which makes stronger the union between ibrutiniband the co-former.

And finally, there is a H-bond between the amine group of ibrutinib andthe carbonyl group of the next ibrutinib molecule.

The calculated atom distances and the angle of the H-bonds:

D—H . . . A D—H (Å) H . . . A (Å) D . . . A (Å) D—H . . . A(°) H-bond 1O4—H45 . . . N5 0.97(3) 1.64 2.582(2) 163(3) H-bond 2 N4—H44 . . . O30.94 2.26 3.164(2) 161(2) H-bond 3 N4—H43 . . . O1 0.92(2) 2.19 2.846(2)127(2)

Example 2: Preparation of Ibrutinib:Fumaric Acid Co-Crystal (2:1)Experiment 1

3 g (6.8 mmol) ibrutinib form A was suspended together with 0.8 g (6.8mmol) fumaric acid in 27 mL MeOH at room temperature (RT). Thesuspension was heated to 70° C. A clear solution was obtained. Thesolution was let slowly cooled down to RT while a white solid started toprecipitate. The precipitate was isolated by filtration and dried at 40°C./10 mbar for 72 hours (Yield: 70%).

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

Experiment 2

Analogous to the Experiment 1, the procedure was performed with 800 mg(1.8 mmol) ibrutinib form A and 210 mg (1.8 mmol) fumaric acid with a43% yield.

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

Experiment 3

1 L reactor was charged with ibrutinib (50 g), fumaric acid (26.35 g)and methanol (350 mL), the mixture was heated to 68° C. untildissolution. The solution was cooled to 45° C. during 1 hour and seededwith ibrutinib:fumaric acid co-crystals. The mixture was cooled to 35°C. during 1 hour and stirred at 35° C. for 2 hours until precipitate wasobtained. The slurry was cooled to 0° C. during 6 hours and stirred at0° C. overnight.

The slurry was filtered under vacuum, washed with cooled methanol (100mL) and dried at 50° C. over 72 hours in vacuum to give 49.46 g of whitesolid (Yield: 87.5%).

The results of Experiments 1 to 3:

¹H-NMR Spectroscopy

The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent,DMSO-d₆ was used. The ¹H-NMR spectrum is shown in FIG. 5. The signalsare summarized below (*=signals of fumaric acid):

1.57 (br. s., 1H); 1.75-2.01 (m, 1H); 2.11 (br. s., 1H); 2.18-2.46 (m,1H); 2.65 (s, 1H); 3.01 (d, J=9.78 Hz, 1H); 3.20 (br. s., 1H); 3.68 (br.s., 1H); 4.06 (d, J=12.12 Hz, 1H); 4.19 (br. s., 1H); 4.52 (br. s., 1H);4.69 (br. s., 1H); 5.57 (d, J=10.17 Hz, 1H); 5.69 (d, J=11.34 Hz, 1H);5.99-6.19 (m, 1H); 6.52-6.63 (m, 1H*); 6.64-6.77 (m, 1H); 6.78-6.98 (m,1H); 7.09-7.19 (m, 4H); 7.31-7.53 (m, 2H); 7.64 (d, J=7.82 Hz, 2H); 8.24(s, 1H); 13.10 (br. s., 1H*).

The integration values of the 1.93 ppm signal (1H) of ibrutinib and the6.60 ppm signal (2H) from fumaric acid were 1 and 1 resp. It correspondswith a ibrutinib:fumaric acid=2:1 molar ratio.

X-Ray Powder Diffraction (XRPD)

The product was characterized by means of x-ray powder diffraction. Itis shown in the FIG. 6.

The x-ray powder diffractogram of ibrutinib:fumaric acid co-crystal ischaracterized by the following signals:

most characteristic peaks [° 2θ] ± 0.2 ° 2θ sample Primarycharacterising peaks Secondary characterising peaks ibrutinib:Fumaricacid 9.9 17.4 18.7 20.5 21.7 6.5 13.0 18.2 22.4 23.9

The complete list of XRPD diffraction peaks of ibrutinib fumaric acidco-crystal (2:1):

Angle ° (2Θ) Relative Intensity % 6.5 3.8% 9.9 14.0% 10.1 4.3% 10.5 3.1%10.8 6.8% 11.9 5.4% 12.6 4.6% 12.8 4.4% 13.0 6.9% 14.7 2.7% 15.2 2.2%17.4 32.8% 18.2 100.0% 18.7 14.6% 19.8 15.0% 20.5 72.4% 21.0 8.5% 21.795.9% 22.4 17.6% 23.6 20.2% 23.9 29.5% 24.4 18.4% 25.2 4.4% 25.7 13.7%26.8 12.4% 28.1 17.7% 29.3 15.4% 30.6 8.3% 31.5 5.4% 32.0 2.9% 33.1 3.7%33.4 4.7% 34.4 2.3% 35.8 8.8% 36.5 4.6% 38.8 3.7% 40.4 3.9% 41.6 5.4%43.4 4.1% 45.6 4.4% 46.8 4.6% 49.1 2.5% 50.2 3.6% 52.6 1.7% 53.5 3.3%

UHPLC/UV

The chromatogram from UHPLC/UV analysis is shown in FIG. 8. Noimpurities were detected (Rt=1.671 min: fumaric acid, Rt=3.728 min:ibrutinib).

Storage Stability of Ibrutinib:Fumaric Acid

One batch of the ibrutinib:fumaric acid cocrystal (stability batch) wasstored in open and closed containers under accelerated conditions. Afterstorage for 4, 8 and 12 weeks, samples were analyzed by UHPLC/UV(chemical purity) as well as by XRPD (solid state stability). Theresults of UHPLC/UV analysis, summarized in the following tabledemonstrate that the chemical purity of the ibrutinib:fumaric acidcocrystal remained unchanged.

Conditions (40° C./75% RH) Open Close 4 Weeks 99.85% 99.93% 8 Weeks99.91% 99.93% 12 Weeks  99.83% 99.90%

The results of XRPD analysis confirmed that the solid state of theibrutinib:fumaric acid cocrystal remained unchanged during storage underaccelerated conditions.

X-Ray Single Crystal Study of Ibrutinib:Fumaric Acid Co-Crystal (2:1)

Temperature 180 K Wavelength 1.54178 Å Crystal system triclinic Spacegroup P1 Unit cell dimensions a [Å] 9.8994 (5) b [Å] 9.9979 (5) c [Å]13.9063 (7) α [°] 93.268 (2) β [°] 99.856 (2) γ [°] 115.655 (2) Volume[Å³] 1208.96 (6)

As is shown in FIG. 9, the packing of ibrutinib:fumaric acid cocrystalconsists of two molecules of ibrutinib in dimeric formation and onemolecule of fumaric acid, i.e. a molar ratio of 2:1 with a triclinicsymmetry. The dimer is formed through hydrogen bonds between N4-H2 andN35 and N34-H4 and N5 of the respective ibrutinib molecules. The amidegroup of ibrutinib establishes H-bonds with the acid group of fumaricacid (both carboxylic groups of fumaric acid are connected with H-bondsto ibrutinib: O61-H5 to O31 and O63-H6 to O6 of the respectivemolecules. Moreover, the ibrutinib dimer is bonded to the next dimer inthe crystal lattice with two H-bonds per molecule: N4-H1 to O31 andN34-H3 to O1. The geometry of fumaric acid clearly shows distancestypical for C═O and C—OH, which are C61-O61 1.329(3) Å, C61-O62 1.197(3)Å, C64-O63 1.312(3) Å and C64-O64 1.207(3) Å.

If the fumaric acid is deprotonated, the distances of C˜O would beapproximately the same distance, reflecting the electron resonance ofthe possible anion.

The calculated atom distances and angles of the H-bonds are thefollowing:

D—H . . . A D—H (Å) H . . . A (Å) D . . . A (Å) D—H . . . A(°) H-bond 1N4—H2 . . . N35 0.899 2.159 3.056(5) 175.28(7) H-bond 2 N34—H4 . . . N50.887 2.000 2.885(5) 175.89(8) H-bond 3 O61—H5 . . . O31 0.897 1.8182.714(5) 178.22(9) H-bond 4 O63—H6 . . . O1 0.907 2.043 2.737(5)132.32(8) H-bond 5 N4—H1 . . . O31 0.878 2.359 3.052(5) 135.92(7) H-bond6 N34—H3 . . . O1 0.873 2.524 3.193(5) 133.98(7)

Stress-Testing of Ibrutinib Co-Crystal with Fumaric Acid

A sample of the Ibrutinib-fumaric acid co-crystal was tested for itspolymorphic stability to extreme conditions. The following conditionswere applied to small samples (about 0.1 g each) of the powderyco-crystal:

-   -   1. 1 minute of 3 tons pressure, using T25 ATLAS power press (by        Specac).    -   2. About 1 minute of strong grinding using pestle and mortar.    -   3. About 1 minute of strong grinding using pestle and mortar        after adding one drop of water to the powder.    -   4. About 1 minute of strong grinding using pestle and mortar        after adding one drop of ethanol to the powder.    -   5. About 1 minute of strong grinding using pestle and mortar        after adding one drop of isopropanol to the powder.    -   6. Heating to 100° C. for 30 minutes.    -   7. 1 week storage under 100% relative humidity at room        temperature.

All the samples were tested in XRPD after the stress-tests. No changewas observed in the XRPD pattern, as shown in FIG. 14.

Example 3: Preparation of Ibrutinib:Succinic Acid Co-Crystal Experiment1

143 mg (0.32 mmol) ibrutinib was suspended together with 156 mg (1.32mmol) succinic acid in 1 mL MeOH at room temperature (RT). A clearsolution was obtained after 5 minutes of stirring. After 60 minutes awhite solid started to precipitate. The solution was let overnight withstirring at RT for the complete precipitation. The precipitate wasisolated by filtration (Yield: 21%).

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

Experiment 2

1 g (2.3 mmol) ibrutinib was suspended together with 1 g (8.5 mmol)succinic acid in 7 mL MeOH at room temperature (RT). A clear solutionwas obtained after 15 minutes of stirring. After 60 minutes, a whitesolid started to precipitate. The solution was let over the weekend withstirring at RT for the complete precipitation. The precipitate wasisolated by filtration (Yield: 67%).

The sample was analysed by means of XRPD and ¹H-NMR spectroscopy.

The results of Experiments 1 to 2:

¹H-NMR Spectroscopy

The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent,DMSO-d₆ was used. The ¹H-NMR spectrum is shown in FIG. 10. The signalsare summarized below (*=signals of succinic acid):

1.57 (br. s., 1H); 1.92 (d, J=13.69 Hz, 1H); 2.12 (br. s., 1H);2.18-2.32 (m, 1H); 2.38 -2.42 (m, 3H*); 2.88-3.07 (m, 1H); 3.10-3.27 (m,1H); 3.70 (d, J=10.56 Hz, 1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s.,1H); 4.54 (d, J=12.12 Hz, 1H); 4.69 (br. s., 1H); 5.57 (d, J=9.78 Hz,1H); 5.69 (d, J=10.56 Hz, 1H); 6.00-6.18 (m, 1H); 6.54-6.77 (m, 1H);6.77-6.98 (m, 1H); 7.09-7.20 (m, 5H); 7.33-7.51 (m, 2H); 7.65 (d, J=7.82Hz, 2H); 8.24 (s, 1H); 12.10 (br. s., 1H*).

The integration values of the 1.92 ppm signal (1H) of ibrutinib and the2.40 ppm signal (4H) from succinic acid were 1 and 2.5 resp.

X-Ray Powder Diffraction (XRPD)

The product was characterized by means of x-ray powder diffraction. Itis shown in the FIG. 11.

The x-ray powder diffractogram of ibrutinib:succinic acid cocrystal ischaracterized by the following signals:

most characteristic peaks [° 2θ] ± 0.2 ° 2θ sample Primarycharacterising peaks Secondary characterising peaks IBT:Succinic acid17.3 17.9 20.2 21.5 21.8 9.8 11.5 13.0 18.3 23.2

The complete list of XRPD diffraction peaks of ibrutinib:succinic acidco-crystal

Angle ° (2Θ) Relative Intensity % 6.5 3.3% 9.8 10.2% 10.2 4.0% 10.8 7.3%11.5 2.7% 12.5 6.3% 13.0 8.5% 14.7 3.3% 15.2 1.7% 15.7 1.2% 17.3 31.3%17.9 49.4% 18.3 97.5% 19.7 16.2% 20.2 100.0% 21.5 67.1% 21.8 76.9% 23.233.1% 23.8 15.9% 24.2 25.2% 25.1 4.3% 26.1 21.3% 26.7 5.4% 27.2 15.1%28.6 11.6% 29.0 13.3% 29.7 7.2% 30.2 10.0% 31.0 7.6% 31.2 8.4% 32.3 5.0%33.4 4.1% 38.1 7.4% 40.7 4.7% 43.0 4.7% 49.5 4.7%

UHPLC/UV

The chromatogram from UHPLC/UV analysis is shown in FIG. 12 (Rt=3.693min: ibrutinib;

succinic acid not detected at this wavelength).

Storage Stability of Ibrutinib: Succinic Acid

One batch of the ibrutinib:succinic acid cocrystal (stability batch) wasstored in open and closed containers under accelerated conditions. Afterstorage for 4, 8 and 12 weeks, samples were analyzed by UHPLC/UV(chemical purity) as well as by XRPD (solid state stability). Theresults of UHPLC/UV analysis, summarized in the following tabledemonstrate that the chemical purity of the ibrutinib:succinic acidcocrystal remained unchanged.

Conditions (40° C./75% RH) Open Close 4 Weeks 99.91 99.91 8 Weeks 99.9199.91 12 Weeks  99.92 99.92

The results of XRPD analysis confirmed that the solid state of theibrutinib:succinic acid cocrystal remained unchanged during storageunder accelerated conditions.

X-Ray Single Crystal Study of Ibrutinib:Succinic Acid Co-Crystal (2:1)

Temperature 180K Wavelength 1.54178 Å Crystal system triclinic Spacegroup P1 Unit cell dimensions a [Å] 10.0016 (3) b [Å] 13.8869 (4) c [Å]18.0873 (5) α [°] 81.479 (1) β [°] 88.755 (1) γ [°] 79.974 (1) Volume[Å³] 2446.48 (7)

The packing of ibrutinib:succinic acid cocrystal in one unit cell in atriclinic symmetry P1 consists of four molecules of ibrutinib and twomolecules of succinic acid, i.e. a molar ratio of 2:1. The packing isstabilised by complex H-bond network of chains formed byIbrutinib:succinic acid:ibrutinib unities. One of the two unities isshown in FIG. 13. The hydrogen atoms were found in relevant positionsclose to the succinic acid. The geometry of succinic acid clearly showsdistances typical for C═O and C—OH, which are C124-O127 1.316(4) Å,C124-O128 1.205(4) Å, C121-O125 1.327(3) Å and C121-O126 1.197(4) Å.

If the succinic acid is deprotonated, the distances of C˜O would beapproximately the same distance, reflecting the electron resonance ofthe possible anion.

The calculated atom distances and angles of the H-bonds from thesuccinic acid to ibrutinib of the two unities in the unit cell are thefollowing:

D—H . . . A D—H (Å) H . . . A (Å) D . . . A (Å) D—H . . . A(°) H-bond 1O127—H1271 . . . O91 0.823 1.894 2.7104) 171.29(17) H-bond 2 O125—H1251. . . O1 0.892 1.838 2.714(4) 166.69(16) H-bond 1 O137—H1371 . . . O610.938 1.802 2.708(4) 161.45(14) H-bond 2 O135—H1351 . . . O31 1.0501.700 2.706(4) 159.00(16)

Example 4: Pharmaceutical Formulations of Ibrutinib Co-CrystalsExperiment 1: Capsules

Ibrutinib:benzoic acid co-crystal 179 mg (corresponds to 140 mg freebase) Aerosil ® 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicifiedmicro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40mg Magnesium stearate 3 mg

Active ingredient and Aerosil were premixed, subsequently all otheringredients except magnesium stearate were blended in a free fall mixerfor 15 min. Then, sieved magnesium stearate was added and the mixturewas blended for further 5 min. The final blend was filled into capsules.

Ibrutinib:fumaric acid co-crystal 158.5 mg (corresponds to 140 mg freebase) Aerosil ® 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicifiedmicro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40mg Magnesium stearate 3 mg

Active ingredient and Aerosil were premixed, subsequently all otheringredients except magnesium stearate were blended in a free fall mixerfor 15 min. Then, sieved magnesium stearate was added and the mixturewas blended for further 5 min. The final blend was filled into capsules.

Experiment 2: Tablets

Ibrutinib:benzoic acid co-crystal 179 mg (corresponds to 140 mg freebase) Aerosil ® 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicifiedmicro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40mg Magnesium stearate 5 mg

Active ingredient and Aerosil were premixed, subsequently all otheringredients except magnesium stearate were blended in a free fall mixerfor 15 min. Then, sieved magnesium stearate is added and the mixture wasblended for further 5 min. The final blend was compressed into tablets.

Ibrutinib:fumaric acid co-crystal 158.5 mg (corresponds to 140 mg freebase) Aerosil ® 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicifiedmicro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40mg Magnesium stearate 5 mg

Active ingredient and Aerosil were premixed, subsequently all otheringredients except magnesium stearate were blended in a free fall mixerfor 15 min. Then, sieved magnesium stearate was added and the mixturewas blended for further 5 min. The final blend was compressed intotablets.

Comparative Example 1: Storage Stability of Ibrutinib Form E Accordingto WO 2013/184572

Ibrutinib free base Form A (1 g) was suspended in toluene (12 mL) andthe resulting slurry was stirred for 3.5 d at room temp. The product wasfiltered off and dried under reduced pressure for 22h to provideIbrutinib free base Form E.

Ibrutinib Form E was stored for twelve weeks at a temperature of 40° C.and a relative humidity of 75%. Ibrutinib Form E transformed intoibrutinib Form A, as shown in FIG. 15 in comparison with the ibrutinibco-crystals according to the invention which remained stable duringstorage. This experiment demonstrates the surprisingly improvedstability of the co-crystals of the invention over the prior art crystalform.

Comparative Example 2: Wettability

The wettability of the below compounds was determined by contact anglemeasurement. For this purpose, the substances were pressed (2 t*cm⁻²) toa pellet. On each pellet were placed three water drops (2 μL) on threeindividual measurement points and the contact angle was measured withthe apparatus OCA40 (DataPhysics Instruments) on two sides of the drop.The determined values are given in table below.

API Form contact angle θ Ibrutinib free base form A 67.9° ± 2.1Ibrutinib fumaric acid 56.8° ± 2.4 Irbutinib succinic acid incapable ofmeasurement* *The contact angle of the co-crystal of ibrutinib andsuccinic acid was incapable of measurement because the wettability ofthis co-crystal is so high that the water drops immediately spread overthe surface and the water sunk into the pellet.

A lower contact angle corresponds to an increase in wettability of thesubstance. An increased wettability facilitates granulation, inparticular wet granulation of the substance. Therefore, as theco-crystals of the present invention have a lower contact angle and,thus, an increased wettability compared to ibrutinib free base, theco-crystals have advantageous properties with respect to furtherprocessing of the compound into pharmaceutical preparations.

What is claimed:
 1. A method of preparing a co-crystal of ibrutinibcomprising the steps of: a. suspending ibrutinib with a carboxylic acidin a suitable solvent, b. heating the obtained suspension until a clearsolution is obtained, c. optionally keeping the obtained solution forsome time and/or under stirring, and d. subsequently cooling thesolution to room temperature.
 2. The method according to claim 1,wherein the solvent is a polar organic solvent.
 3. The method accordingto claim 2, wherein the polar organic solvent is a C1 -C6 aliphaticalcohol.